Current pharmacological therapy for the overweight patient focuses on two approaches: appetite regulation and modulation of intestinal absorption processes. The first approach involves the administration of anoretic agents, such as amphetamines, to the patient in order to control caloric intake. Typically, the amphetamines are used as short term adjuncts to a nutritionally and/or behaviorally designed weight reduction program. While these agents are strong suppressors of appetite, their systemic action is associated with dangerous central nervous system side effects and humoral/neuro-transmitter imbalances.
The second approach to control body weight involves the reduction of the availability of nutrients by affecting digestion and/or absorption. The success of intestinal by-pass operations for the treatment of obesity has encouraged the search for oral agents which might produce a chemically induced, reversible form of altered intestinal absorption. A number of compounds have been examined in studies designed to block the intestinal uptake of lipids. Such an approach, however, disadvantageously causes essential lipid-soluble vitamin malabsorption and other serious disorders (Dobbins, W. O., Herrero, B. A. and Mansbach, C. M., Am. J. Med. Sci. 255 (1968) 63; Bray, G. A., "Drug Therapy for the Obese Patient" in The Obese Patient, (1976) p. 353, Saunders, Philadelphia; and Evans, E., Miller, D. S., Samuel, P. D. and Burland, W. L., Postgrad. Med. J. 51, Suppl. 1 (1975) 1204).
In order to avoid this problem, recent research has been directed toward the development of "starch blockers". An example of these is a preparation of amylase inhibitors which are proposed to block carbohydrate absorption (Keup, V. and Puls, W., Arch. Pharmacol. 297 Suppl. (1975) R85). The rationale for this approach relies on the fact that the enzyme amylase, normally secreted in saliva and from the pancreas, hydrolyzes starch randomly to glucose and maltose. The maltose is then degraded by maltase to the mono-saccharide glucose. The monosaccharides are the only form of any dietary carbohydrate that is absorbed by intestinal transport mechanisms. Thus, if the amylase is inhibited from hydrolyzing the starch, intestinal absorption is blocked. Over 100 different varieties of these "starch blocker" preparations have been placed on the market. They are widely sold by pharmacies and health food stores. The use of these "over-the-counter" offerings has been so attractive that over a million tablets were consumed daily in the United States during the first part of 1982. These consumption figures indicate that the public is remarkably responsive to claims for diet and food supplements promising a short cut to weight control without dietary discipline. Despite the commercial success of these starch blockers, however, there is no evidence that these preparations actually inhibit starch or calorie absorption in vivo. In fact, in a decisive study with human volunteers, Fordran and his coworkers showed no increase in calories lost in feces caused by these amylase inhibitors (Bo-Linn, G. W., Santa Ava, C. A., Morawski, S. G. and Fordran, J. S., New Engl. J. Med. 307 (1982) 1413).
It is generally accepted that the transport system responsible for the active renal reabsorption of D-glucose is localized in the luminal membrane or brush border of proximal tubular cells (see Vick, Diedrich and Baumann, Am. J. of Physiol., Vol. 224, No. 3, March (1973) 552-557). Experimental evidence indicates that the glucose interacts with a component or carrier of the membrane that facilitates the entry of the sugar into the cells. For example, the final step in carbohydrate assimiliation by the small intestine has been shown to be the active absorption of enzyme generated mono-saccharides via a Na.sup.+ -dependent transporter in the epithelial brush border membranes.
Phlorizin is known to be a highly effective and specific blocker of sugar absorption from the intestinal tract. In fact, studies have indicated that this naturally occurring compound found in the bark and other components of apple and other fruit trees is a potent competitive inhibitor of the sugar transport process having an affinity for the sugar transporter of about 1,000 times greater than D-glucose (Bode, F., Baumann, K., and Diedrich, D. F., Biochem. Biophys. Acta 290 (1972) 134). Phlorizin, however, is not a clinically useful and safe pharmacological agent that may be used in the management of diabetic and obese patients.
Orally administered phlorizin not only blocks the in vivo intestinal absorption of glucose in rats and dogs but it also causes a "phlorizin diabetes" or glucosuria. Some of the phlorizin survives the hydrolytic environment of the gastrointestinal tract, is absorbed intact, and is carried to the kidneys where it blocks the sugar transporter. Furthermore, as some of the phlorizin travels through the digestive system, it is hydrolyzed by the intestinal epithelia to phloretin (Diedrich, D. F., Arch. Biochem. Biophys, 127 (1968) 803) which readily enters the blood stream to cause at appropriate levels profound toxic effects at all sites in the body.
While phlorizin is not a clinically useful and safe pharmacological agent, it is a valuable study tool. Tests and studies of phlorizin have shown that the glucose moiety of phlorizin is an essential substituent of a potent sugar uptake inhibitor molecule. Experimental results bear out this postulate with regard to at least a part of this moiety (Diedrich, D. F., "In vitro Evaluation of Relative Inhibitory Potency of Phlorizin and its Congeners", Am. J. Physiol., Vol. 209, No. 3, September (1965)). Clearly, however, since the affinity for the transport site by phlorizin is approximately 1,000 times greater than that shown by glucose, some feature of the aglucone moiety of phlorizin facilitates the interaction of the glucosidic portion of the molecule with the receptor. As a result of the interaction, the stability of the phlorizin formed complex is much greater than that formed with the free sugar.
Further experiments with phlorizin and other structurally related glycosides have resulted in the identification of several features which describe the critical structure of a potent inhibitor of the absorption of glucose. The inhibitory agent is one that possesses atomic groupings in a specific three-dimensional pattern. The pattern favors an association with the membrane receptor. The molecule is visualized to be bound at two or more loci. A primary bond is formed through the interaction of the glycosidic moiety with appropriate groups of the membrane constituent. The linkage presumably is formed through hydrogen bonds that involve at least the hydroxyl groups on C-3 and C-4 of the sugar group. The most stable primary interaction occurs when these hydroxyl groups are situated in the more chemically reactive equatorial position. A secondary bonding of the aglucone portion of the inhibitor molecule to a locus on the biological surface is adjacent to, but removed from the plane of the glucose transporting site. The linkage is probably through hydrogen bonding between the oxygen of the 4-hydroxyphenyl moiety and a membrane constituent capable of serving as a hydrogen donor at physiological pH. The locus is approximately 13-16 .ANG. A removed from the transport site to which glucose is normally bound.
The present invention uses the information gained from the studies of the geometric configuration and chemical structure of the inhibitory mechanism of phlorizin, phloretin and related derivatives and advances the art by providing compounds and compositions having pharmacological efficacies. Particularly the compounds act as pharmacological agents that are clinically useful and safe in inhibiting sugar uptake without systemic side effects.